ClinVar Genomic variation as it relates to human health
NM_002772.3(TMPRSS15):c.2135C>G (p.Ser712Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(7); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002772.3(TMPRSS15):c.2135C>G (p.Ser712Ter)
Variation ID: 4164 Accession: VCV000004164.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q21.1 21: 18312975 (GRCh38) [ NCBI UCSC ] 21: 19685292 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 19, 2017 Oct 20, 2024 Mar 14, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002772.3:c.2135C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002763.3:p.Ser712Ter nonsense NC_000021.9:g.18312975G>C NC_000021.8:g.19685292G>C NG_012207.1:g.95679C>G - Protein change
- S712*
- Other names
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- Canonical SPDI
- NC_000021.9:18312974:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (C)
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Allele frequency
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The frequency of the allele represented by this VCV record.
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1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
The Genome Aggregation Database (gnomAD), exomes 0.00063
The Genome Aggregation Database (gnomAD) 0.00064
Exome Aggregation Consortium (ExAC) 0.00065
Trans-Omics for Precision Medicine (TOPMed) 0.00067
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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TMPRSS15 | - | - |
GRCh38 GRCh37 |
463 | 541 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Mar 14, 2024 | RCV000004381.17 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 10, 2024 | RCV000522000.17 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Oct 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000616897.2
First in ClinVar: Dec 19, 2017 Last updated: Nov 25, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20981092, 11719902, 22344438, 29431110, 1147667, 31980526, 31589614) (less)
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Pathogenic
(Jul 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Enterokinase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175251.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The TMPRSS15 c.2135C>G variant is classified as Pathogenic (PVS1, PM2, PP1) The TMPRSS15 c.2135C>G variant is a single nucleotide change which is predicted to result … (more)
The TMPRSS15 c.2135C>G variant is classified as Pathogenic (PVS1, PM2, PP1) The TMPRSS15 c.2135C>G variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 712. The variant is rare in population databases (gnomAD allele frequency = 0.064%; 98 het and 0 hom in 152120 sequenced alleles; highest frequency = 0.11%, Non-Finnish European population) (PM2). This variant has been reported to segregate with congenital enteropeptidase deficiency in a family with 2 affected siblings (PMID: 11719902) ); PP1). The variant has been reported in dbSNP (rs77200626) and has been reported with Conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 4164). It has not been reported in HGMD. (less)
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Pathogenic
(Jan 20, 2022)
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criteria provided, single submitter
Method: clinical testing
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Enterokinase deficiency
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002022354.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 10, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001418981.3
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ser712*) in the TMPRSS15 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Ser712*) in the TMPRSS15 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMPRSS15 are known to be pathogenic (PMID: 11719902). This variant is present in population databases (rs77200626, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with congenital enteropeptidase deficiency (PMID: 11719902). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4164). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 14, 2024)
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criteria provided, single submitter
Method: clinical testing
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Enterokinase deficiency
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV005016534.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
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Pathogenic
(Oct 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004151040.10
First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024 |
Comment:
TMPRSS15: PVS1, PM3, PM2:Supporting
Number of individuals with the variant: 1
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Uncertain significance
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Enterokinase deficiency
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440221.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
Comment:
This variant was identified as compound heterozygous.
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Pathogenic
(Aug 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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Enterokinase deficiency
(Autosomal recessive inheritance)
Affected status: no
Allele origin:
germline
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Genetic Diagnostics Department, Viafet Genomics Laboratory
Accession: SCV001976441.1
First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
Comment:
As part of Carrier Screening testing performed at Viafet Genomics Laboratory, this variant was identified in a heterozygous state in a patient who is not … (more)
As part of Carrier Screening testing performed at Viafet Genomics Laboratory, this variant was identified in a heterozygous state in a patient who is not affected with this condition. This variant is present in exon 18/25 in the only transcript of this gene. Several loss-of-function variants are reported as disease-causing in HGMD and/or ClinVar after this position. Holzinger et al., 2002 have identified this variant in a compound heterozygous state in 2 siblings affected with Enterokinase deficiency (PMID: 11719902). (less)
Number of individuals with the variant: 1
Secondary finding: yes
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Pathogenic
(Jan 01, 2002)
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no assertion criteria provided
Method: literature only
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ENTEROKINASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024553.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 10, 2018 |
Comment on evidence:
In 2 sibs with enterokinase deficiency (226200) described by Haworth et al. (1975), Holzinger et al. (2002) found compound heterozygosity for mutations in the PRSS7 … (more)
In 2 sibs with enterokinase deficiency (226200) described by Haworth et al. (1975), Holzinger et al. (2002) found compound heterozygosity for mutations in the PRSS7 gene: a 2135C-G mutation in exon 18, resulting in a ser712-to-ter (S712X) substitution, and a 2569C-to-T mutation in exon 22, resulting in an arg857-to-ter substitution (R857X; 606635.0002) within the serine protease domain. Segregation analysis of parental DNA confirmed the compound heterozygosity. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Mutations in the proenteropeptidase gene are the molecular cause of congenital enteropeptidase deficiency. | Holzinger A | American journal of human genetics | 2002 | PMID: 11719902 |
Intestinal enterokinase deficiency. Occurrence in two sibs and age dependency of clinical expression. | Hadorn B | Archives of disease in childhood | 1975 | PMID: 1147667 |
Text-mined citations for rs77200626 ...
HelpRecord last updated Oct 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.